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A method for preparing leuprolide by combining solid phase and liquid phase

A technology of leuprorelin and liquid phase is applied in the field of preparing leuprolide by combining solid phase and liquid phase, which can solve problems such as difficulty in large-scale production and inconvenience, achieve high synthesis yield and avoid product instability. Effect

Active Publication Date: 2022-03-29
浙江湃肽生物股份有限公司南京分公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the synthesis of leuprolide by the existing solid-phase synthesis method, after connecting all amino acids from the carbon end, the liquid ethylamine is used to cut it from the resin. However, the cutting with liquid ethylamine needs to be carried out at low temperature and under pressure. Inconvenient in industrial production, difficult to produce on a large scale

Method used

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  • A method for preparing leuprolide by combining solid phase and liquid phase
  • A method for preparing leuprolide by combining solid phase and liquid phase
  • A method for preparing leuprolide by combining solid phase and liquid phase

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Embodiment 1

[0078] A method for preparing leuprolide by combining solid phase and liquid phase,

[0079] Preparation of the liquid phase carrier: Add potassium carbonate to DMF, then add 3-ethoxy-4-hydroxybenzaldehyde and 2-(2-ethoxyphenoxy)bromoethane, protect with nitrogen, at 70°C Stir the reaction for 24 h at a temperature of 100 °C, add deionized water to precipitate, filter, wash, and dry to obtain benzaldehyde compounds; under nitrogen protection, add benzaldehyde compounds to the tetrahydrofuran solution, add sodium borohydride, The reaction was stirred at high temperature for 6 h. After the reaction was completed, deionized water was added to the solution to precipitate a precipitate, which was filtered, washed, and dried to obtain a liquid phase carrier. The usage amount of potassium carbonate is 1.2 wt% of DMF, the addition amount of 3-ethoxy-4-hydroxybenzaldehyde is 6 wt% of DMF, the addition of 2-(2-ethoxyphenoxy)bromoethane The amount is 9 wt% of DMF, the tetrahydrofuran so...

Embodiment 2

[0094] A method for preparing leuprolide by combining solid phase and liquid phase,

[0095] Preparation of the liquid phase carrier: Add potassium carbonate to DMF, then add 3-ethoxy-4-hydroxybenzaldehyde and 2-(2-ethoxyphenoxy)bromoethane, protect with nitrogen, at 70°C Stir the reaction for 24 h at a temperature of 100 °C, add deionized water to precipitate, filter, wash, and dry to obtain benzaldehyde compounds; under nitrogen protection, add benzaldehyde compounds into the tetrahydrofuran solution, add sodium borohydride, The reaction was stirred at high temperature for 6 h. After the reaction was completed, deionized water was added to the solution to precipitate a precipitate, which was filtered, washed, and dried to obtain a liquid phase carrier. The usage amount of potassium carbonate is 1.2 wt% of DMF, the addition amount of 3-ethoxy-4-hydroxybenzaldehyde is 6 wt% of DMF, the addition of 2-(2-ethoxyphenoxy)bromoethane The amount is 9 wt% of DMF, the tetrahydrofuran ...

Embodiment 3

[0110] A method for preparing leuprolide by combining solid phase and liquid phase,

[0111] Compared with Example 2, the present embodiment is only different in that in the preparation of Fmoc-Arg(Pbf)-Pro-Wang resin, the usage amount of 2-[(3-aminophenyl)sulfonyl)ethanol is DMF 1.9 wt%.

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Abstract

The invention discloses a method for preparing leuprolide by combining a solid phase and a liquid phase, which belongs to the technical field of polypeptide synthesis, and specifically relates to a liquid phase carrier and its application. Hydroxybenzaldehyde and 2-(2-ethoxyphenoxy)bromoethane react in DMF containing potassium carbonate to obtain a liquid phase carrier, and the above-mentioned liquid phase carrier is used to carry out fragment synthesis in the liquid phase; the fragment synthesis obtains Fmoc‑Arg‑Pro‑O‑liquid phase carrier; the product of the above steps is removed from the liquid phase carrier, combined with a solid phase resin, and then coupled with amino acid reagents in the order of the amino acid sequence in leuprolide to obtain leuprolide The leuprolide-based polypeptide resin; after cutting the leuprolide-based polypeptide resin, the leuprolide-based polypeptide is separated, and then ethylaminated to obtain the leuprolide.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular relates to a method for preparing leuprolide by combining a solid phase and a liquid phase. Background technique [0002] Leuprolide is a gonadotropin-releasing hormone analog that is widely used to treat women with precocious puberty, endometriosis, uterine fibroids, or premenopausal breast cancer and men with prostate cancer. The chemical name of leuprolide is 5-oxo-prolyl-histidyl-tryptophanyl-seryl-tyrosyl-D-leucyl-leucyl-arginyl-N-acetyl Base-prolinamide, peptide sequence: H-Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NH-C 2 h 5 , molecular weight 1209.41. In the synthesis of leuprolide by the existing solid-phase synthesis method, after connecting all amino acids from the carbon end, the liquid ethylamine is used to cut it from the resin. However, the cutting with liquid ethylamine needs to be carried out at low temperature and under pressure. It is inconvenien...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/23C07K1/16C07K1/06C07K1/04C07K1/02
CPCC07K7/23
Inventor 章砚东涂仕前魏祝宇潘海良
Owner 浙江湃肽生物股份有限公司南京分公司
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